Worldwide, survival in HIV-infected patients has remarkably improved with the use of highly active anti- retroviral therapy (HAART);however, survival in HIV-infected patients remains decreased compared to the general population in part due to excess deaths from non-infectious illnesses including cardiovascular disease(CVD). At the recent AHA State of the Science Conference on CVD in HIV Patients 2007, experts in cardiology, infectious diseases, endocrinology, and epidemiology agreed that CVD is an emerging problem for HIV patients and a significant need exists for studies to investigate mechanisms and potential therapies. Metabolic effects of ART increase traditionally recognized CV risk factors including dyslipidemia, diabetes mellitus, and central obesity, which are highly prevalent in the HIV population. Beyond these known increased CVD risk factors in HIV-infected patients, the HIV virus itself likely further promotes CVD through increased inflammation, immune activation, and viral factors. Atherosclerosis is an inflammatory disease in which monocytes and T lymphocytes play key roles in atheroma development. HIV infection causes alterations in the monocyte repertoire with expansion of the proinflammatory CD14+CD16+ monocyte subset and T lymphocyte activation. Furthermore, HIV viral factors are being recognized to possibly contribute to atherogenesis. HIV-1 Nef protein impairs efflux of cholesterol from macrophages by downregulation of ATP binding cassette transporter A1 (ABCA1), and thus, promotes foam cell formation. We hypothesize these immune alterations and viral factors promote atherosclerosis development in HIV patients. To further address these questions, we will investigate early measures of atherosclerosis in patients during acute HIV infection and follow these measures longitudinally over time during prolonged HIV infection, hypothesizing that proatherogenic changes will occur in the vascular endothelium during acute infection when viral burden is at its peak. In addition, to investigate potential mechanisms, we will utilize this longitudinal cohort of patients followed from the time of acute HIV infection to investigate the role of proinflammatory alterations of monocyte and T cells by HIV as well as ABCA1 impairment by HIV nef protein as potential key mechanisms we hypothesize to underlie the relationship between HIV infection and atherosclerosis. We further hypothesize that statin therapy will decrease plaque inflammation and have immunomodulatory effects on proinflammatory monocytes and T lymphocyte response in HIV patients. Elucidation of associated atherogenic indices in response to statins will help to guide future strategies of preventive and targeted therapy to decrease CVD in this population. The proposed grant will investigate the effects of the HIV virus and associated changes in the immune system on the development of atherosclerosis during acute HIV infection and after viral suppression with antiretroviral therapy. In addition, the potential beneficial effects of a cholesterol-lowering medication on vascular inflammation and immune cells will be investigated in HIV patients with early asymptomatic atherosclerosis. (End of Abstract)